Electrical inhibition of the phrenic nerve during cardiac pacing

ABSTRACT

According to various method embodiments for pacing a heart and avoiding unwanted stimulation of a phrenic nerve during cardiac pacing, a desired pacing time for delivering a cardiac pace is determined, and a desired nerve traffic inhibition time to inhibit nerve traffic in the phrenic nerve is determined using the desired pace time. The cardiac pace is delivered at the desired pacing time and nerve traffic in the phrenic nerve is inhibited at the desired nerve traffic inhibition time.

CLAIM OF PRIORITY

This application is a divisional of U.S. application Ser. No.12/963,399, filed Dec. 8, 2010, now issued as U.S. Pat. No. 8,620,428,which claims the benefit of priority under 35 U.S.C. §119(e) of U.S.Provisional Patent Application Ser. No. 61/287,308, filed on Dec. 17,2009, which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This application related generally to medical devices and, moreparticularly, to systems, devices and methods for electricallyinhibiting the phrenic nerve.

BACKGROUND

When the heart is paced in the left ventricle (LV), there may beunwanted stimulation of the phrenic nerve that causes contraction of thediaphragm. The left phrenic nerve descends on the pericardium topenetrate the left part of the diaphragm, and in most people, the leftphrenic nerve runs close to the lateral vein. In the clinic, the pacingconfiguration or the stimulation parameters may be modified in an effortto avoid phrenic nerve stimulation. Examples of pacing configurationsinclude LV bipolar, LV to can, LV to RV (right ventricle) also referredto as “extended bipolar”; and examples of stimulation parameters includethe amplitude (e.g. voltage) and pulse width. The anatomic location ofthe phrenic nerve varies within patients. Additionally, the veins arenot always in the same location with respect to the ventricle and thenearby passing nerve. Also, the selected vein in which to place the leadmay vary.

Unintended phrenic nerve activation (an unintended action potentialpropagated in the phrenic nerve) is a well-known consequence of leftventricular pacing. The unintended phrenic nerve activation may causethe diaphragm to undesirably contract. Unintended phrenic nerveactivation may feel like hiccups to the patient. Unintended phrenicnerve activation can occur when the electric field of the LV pacing leadis proximate to the left phrenic nerve and is at a stimulation outputthat is strong enough to capture the nerve. As a consequence, unintendedcapture of the phrenic nerve may require modification of the strategyfor implanting the pacing lead. For example, the LV pacing electrodesmay not be positioned in a preferred position to capture the LV for apacing therapy such as CRT, or the clinician may decide not to implantan LV pacing electrode but rather rely on other pacing algorithms thatdo not pace the LV. A special office visit after implant may benecessary or desirable to reprogram the device to avoid phrenic nervestimulation. Further, although phrenic nerve stimulation is commonlyassessed at implant, unintended phrenic nerve activation caused byphrenic nerve capture during pacing can appear post-implant for avariety of reasons such as reverse remodeling of the heart, leadmicro-dislodgement, changes in posture, and the like.

SUMMARY

Various system embodiments for pacing a heart and avoiding unwantedstimulation of a phrenic nerve include a cardiac pulse generator, anerve traffic inhibitor, a cardiac activity sensor, and a controller.The cardiac pulse generator is configured to generate cardiac paces topace the heart. The nerve traffic inhibitor is configured to generate anelectrical signal to inhibit nerve traffic in the phrenic nerve. Thecardiac activity sensor is configured to sense cardiac activity. Thecontroller is operably connected to the cardiac pulse generator, thenerve traffic inhibitor, and the cardiac activity sensor. The controllerincludes a cardiac pacing timer and a nerve traffic inhibition timer.The controller is configured to use sensed cardiac activity and thecardiac pacing timer to determine a desired pace time for a cardiacpace. The controller is configured to use the desired pace time and anerve traffic inhibition timer to control the nerve traffic inhibitor toinhibit nerve traffic in the phrenic nerve at a desired inhibition timewith respect to the desired pace time to prevent the cardiac pace fromstimulating the phrenic nerve.

According to various method embodiments for avoiding unwantedstimulation of phrenic nerve during cardiac pacing, a desired pace timefor delivering a cardiac pace is received, and a desired nerve trafficinhibition time to inhibit nerve traffic in the phrenic nerve isdetermined using the desired pace time. Nerve traffic in the phrenicnerve is inhibited at the desired nerve traffic inhibition time.

According to various method embodiments for pacing a heart and avoidingunwanted stimulation of a phrenic nerve during cardiac pacing, a desiredpacing time for delivering a cardiac pace is determined, and a desirednerve traffic inhibition time to inhibit nerve traffic in the phrenicnerve is determined using the desired pace time. The cardiac pace isdelivered at the desired pacing time and nerve traffic in the phrenicnerve is inhibited at the desired nerve traffic inhibition time.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Thescope of the present invention is defined by the appended claims andtheir equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are illustrated by way of example in the figures ofthe accompanying drawings. Such embodiments are demonstrative and notintended to be exhaustive or exclusive embodiments of the presentsubject matter.

FIGS. 1A-1E illustrate various implantable device embodiments configuredto stimulate the left ventricle and configured to inhibit phrenic nerveactivity.

FIG. 2 illustrates an embodiment of a lead with annular stimulationelectrodes that form an electrode region, according to variousembodiments.

FIG. 3 illustrates a transluminal neural stimulation using electrodeswithin the lumen, according to various embodiments.

FIGS. 4A and 4B illustrate an embodiment of a lead with stimulationelectrodes, where the illustrated electrodes do not circumscribe thelead.

FIGS. 5A-5E illustrate various signals that provide cardiac pacing andphrenic nerve inhibition using the same electrode, according to variousembodiments of the present subject matter.

FIGS. 6A-6E illustrate a respiratory cycle, cardiac paces, inhibitedleft phrenic nerve activity corresponding to the cardiac paces, anddiaphragm activity when the left phrenic nerve is inhibited for thecardiac pulses.

FIG. 7 illustrates a device embodiment.

FIG. 8 illustrates an embodiment of a method that detects pace-inducedphrenic nerve activation, and performs a phrenic nerve blocking routineto avoid the pace-induced phrenic nerve activation.

FIG. 9 illustrates various embodiments that determine when to implementand when to end a phrenic nerve inhibition process.

FIGS. 10 and 11 illustrate various embodiments for implementing aprocess to reduce phrenic nerve activity.

FIG. 12 illustrates an embodiment of a method for using respiration toenable phrenic nerve traffic inhibition.

FIG. 13 illustrates an embodiment that titrates the intensity orconfiguration of the inhibition stimulation to achieve the desiredphrenic nerve inhibition.

FIG. 14 illustrates a system diagram of an embodiment of amicroprocessor-based implantable device.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an,” “one,” or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

A myocardial stimulation therapy provides a cardiac therapy usingelectrical stimulation of the myocardium. Some examples of myocardialstimulation therapies are provided below. A pacemaker is a device whichpaces the heart with timed pacing pulses, most commonly for thetreatment of bradycardia where the ventricular rate is too slow. Iffunctioning properly, the pacemaker makes up for the heart's inabilityto pace itself at an appropriate rhythm in order to meet metabolicdemand by enforcing a minimum heart rate. Implantable devices have alsobeen developed that affect the manner and degree to which the heartchambers contract during a cardiac cycle in order to promote theefficient pumping of blood. The heart pumps more effectively when thechambers contract in a coordinated manner, a result normally provided bythe specialized conduction pathways in both the atria and the ventriclesthat enable the rapid conduction of excitation (i.e., depolarization)throughout the myocardium. These pathways conduct excitatory impulsesfrom the sino-atrial node to the atrial myocardium, to theatrio-ventricular node, and thence to the ventricular myocardium toresult in a coordinated contraction of both atria and both ventricles.This both synchronizes the contractions of the muscle fibers of eachchamber and synchronizes the contraction of each atrium or ventriclewith the contralateral atrium or ventricle. Without the synchronizationafforded by the normally functioning specialized conduction pathways,the heart's pumping efficiency is greatly diminished. Pathology of theseconduction pathways and other inter-ventricular or intra-ventricularconduction deficits can be a causative factor in heart failure, whichrefers to a clinical syndrome in which an abnormality of cardiacfunction causes cardiac output to fall below a level adequate to meetthe metabolic demand of peripheral tissues. In order to treat theseproblems, implantable cardiac devices have been developed that provideappropriately timed electrical stimulation to one or more heart chambersin an attempt to improve the coordination of atrial and/or ventricularcontractions, termed cardiac resynchronization therapy (CRT).Ventricular resynchronization is useful in treating heart failurebecause, although not directly inotropic, resynchronization can resultin a more coordinated contraction of the ventricles with improvedpumping efficiency and increased cardiac output. A CRT example appliesstimulation pulses to both ventricles, either simultaneously orseparated by a specified biventricular offset interval, and after aspecified atrio-ventricular delay interval with respect to the detectionof an intrinsic atrial contraction or delivery of an atrial pace.

CRT can be beneficial in reducing the deleterious ventricular remodelingwhich can occur in post-MI and heart failure patients, which appears tooccur as a result of changes in the distribution of wall stressexperienced by the ventricles during the cardiac pumping cycle when CRTis applied. The degree to which a heart muscle fiber is stretched beforeit contracts is termed the preload, and the maximum tension and velocityof shortening of a muscle fiber increases with increasing preload. Whena myocardial region contracts late relative to other regions, thecontraction of those opposing regions stretches the later contractingregion and increases the preload. The degree of tension or stress on aheart muscle fiber as it contracts is termed the afterload. Becausepressure within the ventricles rises rapidly from a diastolic toasystolic value as blood is pumped out into the aorta and pulmonaryarteries, the part of the ventricle that first contracts due to anexcitatory stimulation pulse does so against a lower afterload than doesa part of the ventricle contracting later. Thus a myocardial regionwhich contracts later than other regions is subjected to both anincreased preload and afterload. This situation is created frequently bythe ventricular conduction delays associated with heart failure andventricular dysfunction due to an MI. The increased wall stress to thelate-activating myocardial regions is most probably the trigger forventricular remodeling. By pacing one or more sites in a ventricle nearthe infarcted region in a manner which may cause a more coordinatedcontraction, CRT provides pre-excitation of myocardial regions whichwould otherwise be activated later during systole and experienceincreased wall stress. The pre-excitation of the remodeled regionrelative to other regions unloads the region from mechanical stress andallows reversal or prevention of remodeling to occur.

Cardioversion, an electrical shock delivered to the heart synchronouslywith the QRS complex, and defibrillation, an electrical shock deliveredwithout synchronization to the QRS complex, can be used to terminatemost tachyarrhythmias. The electric shock terminates the tachyarrhythmiaby simultaneously depolarizing the myocardium and rendering itrefractory. A class of CRM devices known as an implantable cardioverterdefibrillator (ICD) provides this kind of therapy by delivering a shockpulse to the heart when the device detects tachyarrhythmias. Anothertype of electrical therapy for tachycardia is anti-tachycardia pacing(ATP). In ventricular ATP, the ventricles are competitively paced withone or more pacing pulses in an effort to interrupt the reentrantcircuit causing the tachycardia. Modern ICDs typically have ATPcapability, and deliver ATP therapy or a shock pulse when atachyarrhythmia is detected. ATP may be referred to as overdrive pacing.Other overdrive pacing therapies exist, such as intermittent pacingtherapy (IPT), which may also be referred to as a conditioning therapy.

Both a right phrenic nerve and a left phrenic nerve pass near the heartand innervate the diaphragm below the heart. Various embodimentselectrically inhibit or block nerve traffic in the left phrenic nerveduring LV pacing so as to avoid unintended phrenic nerve activationcaused by stimulation of the phrenic nerve, a common side effect of CRT.Pace-induced phrenic nerve activation may also be observed with otherforms of pacing, particularly LV pacing, because of the close proximityof the LV pacing site to the left phrenic nerve. For example, variousembodiments deliver a selective, nerve-blocking pulse waveform, thatdoes not capture cardiac tissue, before and during pacing of the leftventricle. The inhibition pulse prevents phrenic nerve capture duringthe pacing pulse and thereby prevents activation of the diaphragm.Cardiac stimulation at other locations of the heart may result inunintended phrenic nerve activation in either the left or right phrenicnerve. The present subject matter is not limited to the inhibition ofthe left phrenic nerve during LV pacing, but may be implemented toappropriately address unintended phrenic nerve activation in either theleft or right phrenic nerve caused by cardiac pacing.

The phrenic nerve blocking algorithms can be integrated with knownsensing and pacing algorithms and circuitry. The PN blocking algorithmmay be tailored for individual patients because of anatomicaldifferences in the patient (e.g. the precise location of the phrenicnerve relative to the LV lead). Various embodiments determine the bestelectrode(s) from a plurality of electrodes for use in inhibitingphrenic nerve activity. A multi-polar lead presents more electrodes fromwhich to block, and various embodiments are programmed with an algorithmto help a clinician choose the best electrode from which to block, andto verify that the blocking pulse is effective in alleviating thestimulation of phrenic nerve activity. According to some embodiments,the device is programmed to use sensors to detect unintended phrenicnerve activity or diaphragm contraction and to automatically chooseelectrodes from which to inhibit nerve activity.

Pace-induced phrenic nerve activation may be observed only when apatient is in a particular position (e.g. lying down) or activity level.The unintended phrenic nerve activation may not have been observed atthe time that the stimulation device was implanted because of thepatient position at the time of implantation, because of the effects ofanesthesia, or because of other factors that are not present in aclinical setting. Some embodiments use a posture sensor to providecontext. Some embodiments use an activity sensor to provide context.Some embodiments use a timer to determine a time of day to providecontext. Whenever the context is sensed or otherwise identified orestimated (e.g. any time that the patient is lying down), the device maybe programmed or otherwise configured to respond by initiating aprocedure to inhibit phrenic nerve activity while delivering cardiacpaces. Some embodiments allow the device to store posture, activity,time of day and the like whenever the pace-induced phrenic nerveactivation are detected to determine the context when the unintendedphrenic nerve activation is observed. According to some embodiments, thedevice is configured to use this contextual information to enable aphrenic nerve inhibition routine only during these contextual situationsin which the pace-induced phrenic nerve activation previously occurred.

FIGS. 1A-1E illustrate various implantable device embodiments configuredto stimulate the left ventricle and configured to inhibit phrenic nerveactivity. The illustrated device is an implantable medical device 100used to perform a cardiac tissue stimulation therapy, such as CRT orother pacing therapies, using leads represented by the dotted lines andelectrodes represented by “X” fed into the right atrium, rightventricle, and coronary sinus of the heart. The lead 101 passing throughthe coronary sinus of the heart includes a left ventricular electrode102, or electrodes, for use to stimulate the left ventricle at astimulation site.

In FIG. 1A, the device has a phrenic nerve lead 103 with a nerve cuffelectrode 104. The phrenic nerve lead 103 may be subcutaneously tunneledfrom the device 100 to the phrenic nerve 105, and the device isconfigured to use the phrenic nerve lead 103 and nerve cuff electrode104 to inhibit the phrenic nerve 105. In some embodiments, more than oneimplantable device can be used, where one device provides the cardiactissue stimulation therapy and another device provides the desiredinhibition of the phrenic nerve. The inhibition signal prevents the leftventricle cardiac pace from capturing the left phrenic nerve that passesnear the left ventricular stimulation site. In FIG. 1B, the device 100has a left ventricular lead 106 with a plurality of electrodes 107within a coronary sinus tributary to stimulate at least a first site anda second site. The device 100 is configured to use at least one of theelectrodes 107 to stimulate the first site to deliver left ventricularpaces, and is configured to use at least one other electrode to inhibitnerve traffic in the phrenic nerve 105. Various device embodimentsperform an algorithm that assists the clinician with determining whichof the electrodes to use to inhibit phrenic nerve activity and which ofthe electrodes to use for left ventricular pacing. According to someembodiments, the device is programmed to use sensors to detectunintended phrenic nerve activity or diaphragm contraction and toautomatically choose electrodes from which to inhibit nerve activity. InFIG. 1C, the device 100 has a left ventricular lead 106 with anelectrode 102, wherein the device use electrode 102 positioned with acoronary sinus tributary to both pace the left ventricle and to inhibitthe phrenic nerve. Thus, the same electrode can be used for cardiaccapture and phrenic nerve block, or different electrodes could be usedwhere the different electrodes are either on the same or on differentelectrodes. Any electrode proximate to the phrenic nerve can be used toprovide electrical blocking of the nerve during a cardiac pacing pulse.The electrical blocking of the nerve can be initiated before and/orduring the delivery of the cardiac pacing pulse. In some embodiments,the electrical blocking signal for the phrenic nerve is terminated afterthe cardiac pacing pulse. Some embodiments terminate the electricalblocking during the cardiac pacing pulse, and some embodiments terminatethe electrical blocking just prior to the cardiac pacing pulse. In FIG.1D, the device 100 has a left ventricular leads 106A and B, each with atleast one electrode 102A and B, wherein the device uses electrodes 102Aand B to in a stimulation configuration to inhibit the phrenic nerve.The leads 106A and B are fed into different veins. Some embodiments usemore than one left ventricular lead to inhibit the phrenic nerve. Someembodiments use a bifurcated lead to inhibit the phrenic nerve, wherethe ends of the bifurcated lead extend into the different veins. Someembodiments use other leads (e.g. an RV lead with an LV lead) to inhibitthe phrenic nerve, and some embodiments use a can electrode to inhibitthe phrenic nerve. Some embodiments use epicardial electrodes to inhibitthe phrenic nerve.

According to various embodiments, a selective, nerve-blocking pulsewaveform (sub-cardiac threshold) is delivered before and/or duringpacing of the left ventricle. This pulse will prevent nerve captureduring the pacing pulse and thereby prevent activation of the diaphragm.The electrical inhibition or block of the phrenic nerve can be achievedby: hyperpolarization of the nerve axons using a DC current pulse;depolarization of the nerve axons using a DC current pulse; and/or ahigh-frequency AC waveform (>1 KHz).

A number of electrode configurations can be used. The illustrationsincluded herein are provided as examples, and are not intended to be anexhaustive listing of possible configurations. For example someembodiments use a percutaneous or laparoscopic approach to put anepimysial electrode in the diaphragm near the phrenic nerve or nerves orat other locations near the phrenic nerve(s). FIG. 1E generallyillustrates placement of the epimysial electrode in the diaphragm nearthe phrenic nerve.

FIG. 2 illustrates an embodiment of a lead 208 with annular stimulationelectrodes 209 that form an electrode region 210, according to variousembodiments. Any one or combination of the annular stimulationelectrodes can be used to deliver the neural stimulation. FIG. 3illustrates a transluminal neural stimulation using electrodes within alumen, according to various embodiments. The figure illustrates a lumen311 (e.g. a tributary of the coronary sinus), a phrenic nerve 305external to the lumen, and a lead 308 within the lumen. The neuralstimulation generates an electrical field 312 between the electrodesthat extends past the lumen wall to the nerve. FIGS. 4A and 4Billustrate an embodiment of a lead 413 with stimulation electrodes 414,where the illustrated electrodes do not circumscribe the lead. Thus, asubset of the illustrated electrodes can be selected to providedirectional stimulation. For example, the lead may twist or rotate as itis fed into a coronary sinus tributary, and it may be desired tostimulate a phrenic nerve on one side of the lead without stimulatingtissue on the other sides of the lead. A neural stimulation test routinecan cycle through the available electrodes for use in delivering theneural stimulation to determine which electrodes are most appropriate toblock the phrenic nerve.

There are several ways for delivering an electrical nerve block. In someembodiments, for example, DC current pulses can be applied to the nervemembrane within the electric field of the pulse. A DC pulse canhyperpolarize if its amplitude is below the resting membrane voltage ordepolarize the membrane if its amplitude is above the resting membranevoltage but below the threshold required to generate an actionpotential. Both types of pulses are capable of inducing block bymodifying the excitation properties of the ion channels within the nervemembrane. In another embodiment, for example, a high-frequency waveforme.g. on the order of 1 KHz or greater) is applied, which changes theexcitable status of the nerve membrane under the stimulation field.Various embodiments block the phrenic nerve by stimulating through theclosest electrode(s) to the nerve. Electrical block can be achievedusing high frequency or constant DC pulses. For example, someembodiments deliver a high (frequency or amplitude) pulse that startsduring the refractory period of the heart, avoiding capture of themyocardium and then ramps down to a low frequency or amplitude levelduring the pacing pulse, thus allowing cardiac response but maintainingphrenic nerve block.

FIGS. 5A-5E illustrate various signals that provide cardiac pacing andphrenic nerve inhibition using the same electrode, according to variousembodiments of the present subject matter. FIG. 5A illustrates abiphasic cardiac pace 515 preceded by an inhibition pulse 516 thatprovides a constant depolarizing DC pulse that blocks the nerve axons inanticipation of the cardiac pace. FIG. 5B illustrates a biphasic cardiacpace 517 preceded by a constant hyperpolarizing DC pulse 518 that blocksthe nerve axons before the cardiac pacing pulse. FIG. 5C illustrates abiphasic cardiac pace 519 preceded by an inhibition signal 520 thatincludes a high-frequency waveform (e.g. on the order of 1 KHz orgreater), which blocks the nerve axons in anticipation of the cardiacpacing pulse. FIG. 5D illustrates a signal 521 that delivers a cardiacpace and inhibits phrenic nerve activity simultaneously. The amplitudeof the pace 521 is similar to the amplitude of the biphasic paces 515,517 and 519, and the pulse frequency of the pulses within the pace issimilar to high pulse frequency of the inhibition signal 520. FIG. 5Eillustrates another signal that delivers a cardiac pace and inhibitsphrenic nerve activity simultaneously. The signal illustrates a biphasicpulse for cardiac pacing, such as illustrated at 517 in FIG. B, with ahigh frequency signal for phrenic nerve inhibition superimposed on thebiphasic pulse. FIGS. 5A-5E illustrate square waves. However, thepresent subject matter may use other waveforms, such as sinusoidal andtriangular waveforms by way of example and not limitation.

Regardless of whether the inhibition pulse and the cardiac pace aredelivered by the same or different pulses, the cardiac pace is deliveredat a desired pacing time, and the nerve traffic is inhibited in thephrenic nerve at a desired nerve traffic inhibition time. The desiredpace time is determined by the pacing algorithm, and the desired pacetime is used to determine the desired nerve traffic inhibition time toappropriately inhibit or block phrenic nerve activity when the cardiacpace is delivered.

Respiration involves both voluntary and involuntary actions. Musclesused in respiration include the diaphragm, intercostal, and abdominalmuscles. The intercostal muscles provide expiratory and inspiratoryfunctions, the abdominal muscles have an expiratory function, and thediaphragm provides an inspiratory function. Phrenic nerve activitycontrols the diaphragm, and is primarily active during the inspirationphase of the respiratory cycle. There may be some residual phrenic nerveactivity after the inspiration phase. Respiration is a complex processinvolving many physiologic responses. For example, phrenic nerveactivity is inhibited by lung volume-related afferents. Additionally,the diaphragm is innervated by a left and a right phrenic nerve. If oneof the phrenic nerves has been severed, the other phrenic nervecontinues to cause the diaphragm to contract (inspiration) to providebreathing, albeit more labored than if both phrenic nerves arefunctional.

FIGS. 6A-6E illustrate a respiratory cycle, cardiac paces, inhibitedleft phrenic nerve activity corresponding to the cardiac paces, anddiaphragm activity when the left phrenic nerve is inhibited for thecardiac pulses. These figures are illustrative in nature, and are notdrawn to scale.

The respiratory signal is a physiologic signal indicative of respiratoryactivities. In various embodiments, the respiratory signal includes anyphysiology signal that is modulated by respiration. In one embodiment,the respiratory signal is a transthoracic impedance signal sensed by animplantable impedance sensor. In another embodiment, the respiratorysignal is extracted from a blood pressure signal that is sensed by animplantable pressure sensor and includes a respiratory component. Inanother embodiment, the respiratory signal is sensed by an externalsensor that senses a signal indicative of chest movement or lung volume.According to various embodiments, peaks of a respiratory signal aredetected as respiratory fiducial points. Respiration fiducial points canbe used, either with or without a delay interval, to time the deliveryof the phrenic nerve inhibition. In various other embodiments, onsetpoints of the inspiration phases, ending points of the expirationphases, or other threshold-crossing points are detected as therespiratory fiducial points.

FIG. 6A illustrates a respiratory signal including respiratory cyclelength, inspiration period, expiration period, non-breathing period, andtidal volume. By way of example, a respiratory variability can bedetermined using one or more of the parameters illustrated in thefigure. The axes of the graph are volume and time, such that the signalrepresents the respiration volume over time. The inspiration periodstarts at the onset of the inspiration phase of a respiratory cycle,when the amplitude of the respiratory signal rises above an inspirationthreshold, and ends at the onset of the expiration phase of therespiratory cycle, when the amplitude of the respiratory cycle peaks.The expiration period starts at the onset of the expiration phase andends when the amplitude of the respiratory signal falls below anexpiration threshold. The non-breathing period is the time intervalbetween the end of the expiration phase and the beginning of the nextinspiration phase. The tidal volume is the peak-to-peak amplitude of therespiratory signal. The respiratory rate can be determined from thecycle length: rate (br/min)=1/(cycle length) when the cycle length isprovided in the units of minutes.

FIG. 6B illustrates a series of left ventricle (LV) paces 624. FIGS. 6Aand 6B illustrate, by way of example and not limitation, about fourcardiac cycles for each respiratory cycle. The phrenic nerve traffic isappropriately inhibited to prevent the LV paces from inducing phrenicnerve activity. By way of example and not limitation, some embodimentsinitiate nerve traffic inhibition a small time period before theanticipated LV pace 624 and for a duration extending to the end of theLV pace.

FIG. 6C illustrates the inspiration period 625, and further illustratesthe phrenic nerve inhibition or block 626 such as may be delivered forat least some of the LV paces 624. The phrenic nerve activitypredominately occurs during the inspiration period. Thus, FIG. 6Cillustrates time periods of intrinsic phrenic nerve activity, and timeperiods when that intrinsic activity may be blocked according to someembodiments of the present subject matter. Phrenic nerve blocks outsideof the inspiration period would not significantly affect respiration, asthere is only some residual nerve traffic in other periods of therespiration cycle.

FIG. 6D illustrates diaphragm activity 627, which generally correspondsto the respiration cycle, and also illustrates the ramp-like integratedphrenic nerve activity 628 that occurs during respiration. FIG. 6Eillustrates phrenic nerve activity for a respiratory cycle. The regionsof the nerve blocking pulses that occur during inspiration areillustrated generally at 629, 630 and 631. FIG. 6C also illustratesother nerve blocking pulses throughout the respiratory cycle, and thetimes associated with these nerve blocking pulses are reflected in FIG.6D. It is expected that the diaphragm activity will be affected slightlyat regions 629 and 630. However, the time duration of these regions 629and 630 is short in comparison to the over all respiratory cycle.Further, there is a cumulative recruitment of diaphragm muscle fibersduring the inspiration process. Additionally, the other phrenic nerve(e.g. right phrenic nerve) continues to function to contract portions ofthe diaphragm that it innervates, as labored breathing can still occurif one of the phrenic nerves has been severed. Thus, it is expected thatthe diaphragm's contraction ability will not be affected during thephrenic nerve blocking pulse because the inhibition applied by thealgorithm will be intermittent and of a short duration, and because theother phrenic nerve will remain active. The integrated phrenic nerveactivity 628 is illustrated with a plateau corresponding to the timeduration of the phrenic nerve blocking pulse region 629.

Blocking the phrenic nerve outside of the inspiration period for arespiration cycle may not significantly affect respiration, as theseportions of the respiration cycle may not have significant intrinsicphrenic nerve traffic. Thus, a phrenic nerve blocking pulse wouldprevent cardiac paces from causing diaphragmatic stimulation duringthese portions of the respiration cycle without drastically affectingthe respiration cycle. Further, some intrinsic phrenic nerve activitymay be inhibited by the intrinsic physiology (e.g. by lungvolume-related afferents) during portions of the respiratory cycle.During these portions of the respiratory cycle, it may or may not benecessary to use phrenic nerve blocking pulses to further inhibit thediaphragmatic stimulation caused by cardiac paces. Also, certainportions of the inspiration period will have very significant phrenicnerve activity, e.g. at the end of the inspiration phase during deepbreathing. If the diaphragm is fully contracted at such a time in therespiratory cycle, then it may not be expected that a cardiac pace wouldcause diaphragmatic stimulation. In addition, there may be periods inthe respiratory cycle during which the distance between the phrenicnerve and the cardiac pacing lead is increased such that the electricfield produced by the cardiac pacing pulse is not strong enough toelicit a diaphragmatic response via the phrenic nerve. Changes in thisdistance could be a result of lung-volume-induced changes in theanatomical alignment of the organs in the mediastinum or of changes inbody position. Based on these and other factors, only certain portionsof the respiratory cycle may be susceptible to cardiac-pace-induceddiaphragmatic stimulation. Some embodiments do not administer a blockingpulse (e.g. are not enabled) during certain phases of respiratory cycle(e.g. where unhampered diaphragm activation is desired, or where theintrinsic physiology makes it unlikely that the cardiac pace willstimulate the nerve). Thus, for certain patients, phrenic nerve blockingcould be enabled with respiratory and other physiological sensing.

FIG. 7 illustrates a device embodiment. The illustrated device 740includes a controller 741, a cardiac pulse generator 742, a nerveblocking stimulator 743 and a cardiac activity sensor 744. The device isconfigured to implement a cardiac pacing algorithm. The controller 741receives sensed cardiac activity from the cardiac activity sensor, anduses a cardiac pacing timer 745 to determine a pace time for deliveringa cardiac pace and controls the cardiac pulse generator 742 to deliverthe cardiac pace at the desired time. The controller 741 also includes anerve blocking or inhibition stimulation timer 746 to determine aninhibition time for delivering phrenic nerve inhibition, and controlsthe nerve blocking stimulator 743 to generate the phrenic nerveinhibition at the inhibition time. The nerve blocking stimulator 743 isconfigured to deliver an appropriate electrical signal according to aprotocol to effectively block or inhibit the phrenic nerve traffic.Protocol examples include a DC current pulse to hyperpolarize nerveaxons in the phrenic nerve at the desired inhibition time, adepolarizing DC current pulse to modify the excitability of the nerveaxons in the phrenic nerve at the desired inhibition time but withoutenough strength to generate propagated action potentials, and pulses ata pulse frequency greater than 1 KHz. In some embodiments, thecontroller is configured to implement a nerve traffic blocking algorithmonly as need. For example, other sensor(s) 747 may be used to detect apace-induced phrenic nerve activity, respiratory cycles, posture,activity, and the like.

FIGS. 8-13 illustrate various methods embodiments. FIG. 8, for example,illustrates a method which detects pace-induced phrenic nerve activity,and performs a phrenic nerve blocking routine to avoid the pace-inducedphrenic nerve activity. At 848, it is determined whether previouspace(s) capture the phrenic nerve. For example, diaphragm contractionfrom phrenic nerve activity may be detected by an accelerometer oracoustic sensor, and the timing of the sensed diaphragm contraction iscompared to the timing of a cardiac pace to determine if the cardiacpace likely caused the phrenic nerve activity. Additional confidence canbe obtained by comparing multiple diaphragm contractions to multiplepaces. If it is determined that the pace is inducing unwanted phrenicnerve activity (PN capture), then a process is implemented to reducephrenic nerve activity to avoid capture of the phrenic nerve 849. Thedevice can be programmed to verify whether the phrenic nerve is stillcaptured after a period of time or after a number of paces or after achange in a contextual event such as a change from lying down tostanding up.

FIG. 9 illustrates various embodiments that determine when to implementand when to end a phrenic nerve inhibition process. At 950, it isdetermined whether to enable or otherwise implement a phrenic nervetraffic blocking or inhibition algorithm. For example, posture, time ofday, and/or a detected capture of the phrenic nerve may be used toenable the process. At 951, the process to reduce phrenic nerve activityto avoid phrenic nerve capture is implemented. At 952, it is determinedwhether to end the process because the duration of the process extendsto a particular period of time or a number of pace cycles, or because acontextual event (e.g. posture or activity) changed.

FIGS. 10 and 11 illustrate various embodiments for implementing aprocess to reduce phrenic nerve activity. A cardiac pacing algorithm,for example, determines that a pace will be provided and when the pacewill be provided 1053 and 1153. Rather than being integrated with a CRMsystem, some embodiments may be implemented as a stand alone nervetraffic inhibitor. Such embodiments need not determine when the pacewill be provided, but rather may just receive a desired cardiac pacetime from the CRM system. Some embodiments inhibit phrenic nerveactivity 1054 before the pace is provided 1055 as illustrated in FIG. 10and some embodiments inhibit phrenic nerve activity 1154 as the pace isbeing provided 1155 as illustrated in FIG. 11.

FIG. 12 illustrates an embodiment of a method for using respiration toenable phrenic nerve traffic inhibition. At 1256, it is determinedwhether a cardiac pace will be provided and a cardiac pace time fordelivering the pace. At 1257, the determined pace time is compared tothe respiration cycle, and this comparison is used to determine whetherthe respiration cycle enables the inhibition of the phrenic nerve 1258.If the pace time is at an appropriate time in the respiratory cycle,then the phrenic nerve activity is inhibited 1259.

Various embodiments titrate the blocking stimulation, as the thresholdto block phrenic nerve activity may change with time (due to reverseremodeling for example), position, and the like. Examples of adjustingstimulation can be found in U.S. Pat. No. 6,772,008 entitled Method andApparatus for Avoidance of Phrenic Nerve Stimulation During CardiacPacing”, U.S. Pat. No. 7,299,093 entitled “Method and Apparatus forAvoidance of Phrenic Nerve Stimulation During Cardiac Pacing”, U.S. Pat.No. 7,392,086 entitled “Implantable Cardiac Device and Method forReduced Phrenic Nerve Stimulation”, and Gurevitz et al. entitled“Programmable Multiple Pacing Configurations Help to Overcome High LeftVentricular Pacing Thresholds and Avoid Phrenic Nerve Stimulation”,Pace, Vol. 28, 1255 (2005). These references (U.S. Pat. Nos. 6,772,008,7,299,093, 7,392,086 and Gurevitz et al.) are incorporated herein byreference in their entirety. FIG. 13 illustrates an embodiment thattitrates the intensity or configuration of the inhibition stimulation toachieve the desired phrenic nerve inhibition. At 1360, stimulation isdelivered to inhibit phrenic nerve traffic. If phrenic nerve activity isblocked or inhibited, at 1361, the stimulation to inhibit phrenic nervetraffic continues at 1362. If phrenic nerve activity is not blocked orinhibited, the stimulation intensity (e.g. amplitude) or stimulationconfiguration between or among electrodes are adjusted at 1363. It canbe determined whether the phrenic nerve activity is sufficiently blockedby determining if pace-induced phrenic nerve activity is detected whenthe inhibition stimulation is being delivered.

FIG. 14 illustrates a system diagram of an embodiment of amicroprocessor-based implantable device. The controller of the device isa microprocessor 1464 which communicates with a memory 1465 via abidirectional data bus. The controller could be implemented by othertypes of logic circuitry (e.g., discrete components or programmablelogic arrays) using a state machine type of design. As used herein, theterm “circuitry” should be taken to refer to either discrete logiccircuitry or to the programming of a microprocessor. Shown in the figureare three examples of sensing and pacing channels designated “A” through“C” comprising bipolar leads with ring electrodes 1466A-C and tipelectrodes 1467A-C, sensing amplifiers 1468A-C, pulse generators1469A-C, and channel interfaces 1470A-C. In some embodiments, the leadsof the cardiac stimulation electrodes are replaced by wireless links.Each channel thus includes a pacing channel made up of the pulsegenerator connected to the electrode and a sensing channel made up ofthe sense amplifier connected to the electrode. The channel interfacescommunicate bidirectionally with the microprocessor, and each interfacemay include analog-to-digital converters for digitizing sensing signalinputs from the sensing amplifiers and registers that can be written toby the microprocessor in order to output pacing pulses, change thepacing pulse amplitude, and adjust the gain and threshold values for thesensing amplifiers. The sensing circuitry of the pacemaker detectsintrinsic chamber activity, termed either an atrial sense or ventricularsense, when an electrogram signal (i.e., a voltage sensed by anelectrode representing cardiac electrical activity) generated by aparticular channel exceeds a specified detection threshold. Pacingalgorithms used in particular pacing modes employ such senses to triggeror inhibit pacing. The intrinsic atrial and/or ventricular rates can bemeasured by measuring the time intervals between atrial and ventricularsenses, respectively, and used to detect atrial and ventriculartachyarrhythmias.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 1471 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in anextended bipolar or in a unipolar mode using only one of the electrodesof the lead with the device housing (can) 1472 or an electrode onanother lead serving as a ground electrode. A shock pulse generator 1473is also interfaced to the controller for delivering a defibrillationshock via a pair of shock electrodes 1474 and 1475 to the atria orventricles upon detection of a shockable tachyarrhythmia. A canelectrode may be used to deliver shocks.

Neural stimulation channels, identified as channels D and E, areincorporated into the device, where one channel includes a bipolar leadwith a first electrode 1476D and a second electrode 1477D, a pulsegenerator 1478D, and a channel interface 1479D, and the other channelincludes a bipolar lead with a first electrode 1476E and a secondelectrode 1477E, a pulse generator 1478E, and a channel interface 1479E.Other embodiments may use unipolar leads in which case the neuralstimulation pulses are referenced to the can or another electrode. Thepulse generator for each channel outputs a train of neural stimulationpulses which may be varied by the controller as to amplitude, frequency,duty-cycle, and the like. In this embodiment, each of the neuralstimulation channels uses a lead which can be intravascularly disposednear an appropriate neural target. Other types of leads and/orelectrodes may also be employed. A nerve cuff electrode may be used inplace of an intravascularly disposed electrode to provide neuralstimulation. In some embodiments, the leads of the neural stimulationelectrodes are replaced by wireless links. The figure illustrates atelemetry interface 1479 connected to the microprocessor, which can beused to communicate with an external device.

Various embodiments include one or more of the following: a pace-inducedphrenic nerve activity detector 1481 to detect phrenic nerve capture, arespiration detector 1482 and/or other sensor(s) 1483 such as to providecontextual information like activity and posture. According to variousembodiments, the phrenic nerve activity detector may include, but is notlimited to, an accelerometer, an acoustic sensor, a respiration sensor,impedance sensors, neural sensor on the phrenic nerve, or electrodes tosense electromyogram signals indicative of diaphragm contraction.Various embodiments use more than one detector to provide a compositesignal that indicates phrenic nerve capture. The illustrated embodimentalso includes a clock 1484.

The illustrated microprocessor 1464 is capable of performing phrenicnerve traffic inhibition routines 1485, and cardiac tissue (e.g.myocardial) stimulation routines 1486. Examples of phrenic nerve trafficinhibition routines include hyperpolarization the nerve axons using a DCcurrent pulse; depolarization of the nerve axons using a DC currentpulse; and/or a high-frequency AC waveform (>1 KHz). Examples ofmyocardial therapy routines include bradycardia pacing therapies,anti-tachycardia shock therapies such as cardioversion or defibrillationtherapies, anti-tachycardia pacing therapies (ATP), and cardiacresynchronization therapies (CRT). The illustrated controller is able toperform routines 1487 to integrate myocardial stimulation with phrenicnerve traffic inhibition to avoid pace-induced phrenic nerve activity.The illustrated controller 1464 also includes a comparator 1488 tocompare time when phrenic nerve activity is detected to a pace time todetermine that the phrenic nerve activity is attributed to the pace. Thecontroller 1464 also includes a comparator 1489 to compare respirationfeatures to the pace time, and enable the phrenic nerve trafficinhibition if the pace time occurs during a programmed time of therespiration.

The neural stimulation to inhibit phrenic nerve activity and cardiacrhythm management functions may be integrated in the same device, asgenerally illustrated in FIG. 14 or may be separated into functionsperformed by separate devices.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, firmware and combinations thereof.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. In variousembodiments, the methods are implemented using a sequence ofinstructions which, when executed by one or more processors, cause theprocessor(s) to perform the respective method. In various embodiments,the methods are implemented as a set of instructions contained on acomputer-accessible medium such as a magnetic medium, an electronicmedium, or an optical medium.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

What is claimed is:
 1. A method for avoiding unwanted stimulation of aphrenic nerve during cardiac pacing, comprising: receiving a desiredpace time for delivering a cardiac pace; determining a desired nervetraffic inhibition time to inhibit nerve traffic in the phrenic nerve,wherein determining the desired nerve traffic inhibition time includesusing the desired pace time to determine the desired nerve trafficinhibition time; and inhibiting nerve traffic in the phrenic nerve atthe desired nerve traffic inhibition time by delivering an electricalwaveform to the phrenic nerve that modifies excitability of nerve axonsin the phrenic nerve to inhibit nerve traffic in the phrenic nerve. 2.The method of claim 1, wherein inhibiting nerve traffic includes:delivering a DC current pulse to hyperpolarize nerve axons in thephrenic nerve at the desired inhibition time; or delivering adepolarizing DC current pulse to modify the excitability of nerve axonsin the phrenic nerve at the desired inhibition time but without enoughstrength to generate propagated action potentials; or delivering pulsesat a pulse frequency where the frequency is effectively high to modifythe excitability of the nerve axons in the phrenic nerve at the desiredinhibition time.
 3. The method of claim 1, wherein inhibiting nervetraffic includes using at least one electrode in a coronary sinustributary to inhibit nerve traffic in the phrenic nerve.
 4. The methodof claim 1, further comprising detecting pace-induced phrenic nerveactivity, and wherein inhibiting nerve traffic includes implementing aprocess, in response to detecting the pace-induced phrenic nerveactivity, to inhibit nerve traffic in the phrenic nerve.
 5. The methodof claim 1, further comprising detecting a respiration cycle, whereininhibiting nerve traffic includes implementing a process to inhibitnerve traffic only for a portion of the detected respiration cycle.
 6. Amethod for pacing a heart and avoiding unwanted stimulation of a phrenicnerve during cardiac pacing, comprising: determining a desired pacingtime for delivering a cardiac pace; determining a desired nerve trafficinhibition time to inhibit nerve traffic in the phrenic nerve, whereindetermining the desired nerve traffic inhibition time includes using thedesired pace time to determine the desired nerve traffic inhibitiontime; and delivering the cardiac pace at the desired pacing time andinhibiting nerve traffic in the phrenic nerve at the desired nervetraffic inhibition time by delivering an electrical waveform to thephrenic nerve that modifies excitability of nerve axons in the phrenicnerve to inhibit nerve traffic in the phrenic nerve.
 7. The method ofclaim 6, wherein: delivering the cardiac pace includes delivering thecardiac pace to a left ventricle of the heart; and inhibiting nervetraffic in the phrenic nerve includes inhibiting nerve traffic in a leftphrenic nerve.
 8. The method of claim 7, further comprising deliveringcardiac resynchronization therapy (CRT), wherein delivering the CRTincludes delivering the cardiac pace to a left ventricle of the heart.9. The method of claim 7, further comprising using a common lead withina coronary sinus tributary to deliver the cardiac pace to the leftventricle and to inhibit nerve traffic in the left phrenic nerve. 10.The method of claim 6, wherein the desired nerve traffic inhibition timeis initiated before or during the desired pace time.
 11. A method foravoiding unwanted stimulation of a phrenic nerve during cardiac pacing,comprising: determining a desired nerve traffic inhibition time toinhibit nerve traffic in the phrenic nerve, wherein determining thedesired nerve traffic inhibition time includes using a desired pace timefor the cardiac pacing to determine the desired nerve traffic inhibitiontime; and inhibiting nerve traffic in the phrenic nerve at the desirednerve traffic inhibition time by delivering an electrical waveform tothe phrenic nerve that modifies excitability of nerve axons in thephrenic nerve to inhibit nerve traffic in the phrenic nerve.
 12. Themethod of claim 11, wherein delivering the electrical waveform to thephrenic nerve includes delivering a hyperpolarizing DC current pulse.13. The method of claim 11, wherein delivering the electrical waveformto the phrenic nerve includes delivering a depolarizing DC currentpulse.
 14. The method of claim 11, wherein delivering the electricalwaveform to the phrenic nerve includes delivering pulses at a frequencyeffectively high to modify the excitability of the nerve axons in thephrenic nerve at the desired inhibition time.
 15. The method of claim11, wherein inhibiting nerve traffic includes using at least oneelectrode in a coronary sinus tributary to inhibit nerve traffic in thephrenic nerve.
 16. The method of claim 11, further comprising detectingpace-induced phrenic nerve activity, and wherein inhibiting nervetraffic includes implementing a process, in response to detecting thepace-induced phrenic nerve activity, to inhibit nerve traffic in thephrenic nerve.
 17. The method of claim 11, further comprising detectinga respiration cycle, wherein inhibiting nerve traffic includesimplementing a process to inhibit nerve traffic only for a portion ofthe detected respiration cycle.
 18. The method of claim 11, furthercomprising determining the desired pacing time for delivering a cardiacpace, and delivering the cardiac pace at the desired pacing time. 19.The method of claim 11, further comprising a physiological sensor or aclock to detect a contextual event, wherein inhibiting nerve traffic inthe phrenic nerve at the desired nerve traffic inhibition time includesenabling an ability to inhibit nerve traffic in the phrenic nerve for atime period after the contextual event.
 20. The method of claim 11,further comprising detecting a respiration cycle, and using the detectedrespiration cycle to determine the desired nerve traffic inhibitiontime.